In the proposed studies, the physical interaction that occurs between the catalytic subunit of HSV polymerase and its processivity factor UL42 will be characterized in detail. A sequence encoding a peptide corresponding to the C-terminal 36 residues of polymerase, which mediate UL42 binding, will be mutagenized and the ability of mutants to bind UL42 will be quantified using a yeast or bacterial two-hybrid system. The helicity Of these peptides and their ability to inhibit processivity will be examined. These studies will characterize the role of the helix-loop-helix structure formed by the C-terminal 36 residues of polymerase in UL42 binding. The region of UL42 between residues 160 and 190 will also be mutagenized and tested for binding activity in a two- hybrid system. The ability of UL42 mutants to stimulate processivity will be determined. These studies will indicate if the polymerase binding site lies within a contiguous region of UL42. The information gained from these studies will be used in the rational design of compounds that inhibit polymerase/UL42 binding. A combinatorial approach to drug discovery will also be taken by using phage display to identify binding inhibitors.